Insulin dependent diabetes mellitus is caused by the autoimmune destruction of insulin producing beta cells from the islets of Langerhans in the pancreas. There is no cure for the disease following the actual clinical onset. Therapy utilizing monoclonal antibodies that signaling of the CD40 molecule may become important avenues for prevention of the disease process. Indeed, it has been demonstrated that treatment of NOD mice with such blocking antibodies completely protects them from both diabetes development and destructive inflammation of the pancreatic islets. In this application we propose to study the role of CD40/CD40L interactions in the development of IDDM. We will determine the effects of CD40 signaling on the activation of antigen presenting cells. We will also study the regulatory capacity of the T cells and antigen presenting cells from models where CD40 signaling is blocked. Lastly we will determine whether CD40 signaling is required for the bystander response that mediates IDDM induced by Coxsackie virus infection. These studies will illuminate the mechanisms that underlie the participation of the CD40/CD40L interaction in the development of autoimmunity and will further our goal establishing treatment for IDDM patients.